探讨努南综合征(NS)的临床特点及遗传学特征，以及采取重组人生长激素(rhGH)治疗NS患儿的疗效及安全性。

选择2021年1月至2023年2月于蚌埠医科大学第一附属医院确诊的患儿1～4及患者5为研究对象。其中，患儿1～4为儿童NS患儿，患儿3、4为胞兄弟，患者5为患儿3、4的母亲。因胞兄(患儿3)生长缓慢，胞兄弟(患儿3、4)及母亲(患者5)于本院儿童内分泌科进行家系基因检测，未对患儿4、患者5完善其他相关检查。对患儿1～3和患者5进行高通量测序，并且采用Sanger测序法验证，患儿4仅进行Sanger测序。采用回顾性研究方法，对患儿1～4及患者5的临床病例资料进行分析，包括临床表现、入院检查结果、基因检测结果、治疗与随访结果等。本研究遵循的程序符合蚌埠医科大学第一附属医院伦理审查委员会的规定，通过该委员会审查及批准(批准文号：2023YJS141)，并取得所有患者或其监护人的知情同意。

本研究患儿1～4及患者5的临床资料分析结果如下。①病史采集与体格检查结果：4例(患儿1～4)为男性，1例(患者5)为女性。4例(患儿1～4)有NS特殊面容，1例(患者5)无明显特殊面容；4例(患儿1～3与患者5)合并先天性心脏病(CHD)，其中患儿1合并肺动脉狭窄，患儿2合并动脉导管未闭与室间隔缺损，患儿3合并肺动脉狭窄与房间隔缺损，患者5合并房间隔缺损；患儿1～3合并身材矮小；患者5有双子宫、缺铁性贫血。②患儿1～3的实验室及影像学检查结果：患儿3胰岛素水平<2 mIU/L、胰岛素样生长因子(IGF)-1水平<25 ng/mL，均较正常值低，患儿1～3其余实验室检查结果，均未见异常；患儿3下丘脑、垂体MRI检查结果提示左侧颞极蛛网膜囊肿，患儿2脊柱轻度侧弯，患儿1～3其余影像学检查结果均未见异常。③基因检测结果：患儿1发生LZTR1基因c.851G>A(p.R284H)可能致病性变异，来源于父亲；患儿2发生LZTR1基因c.1943-256C>T致病性变异，其父母均为野生型；患儿3～4及患者5均发生SOS1基因c.1654A>G(p.R552G)致病性变异，患儿3～4该变异来源于其母亲(患者5)，患者5该变异来源不详。④治疗与随访结果：2例患儿(患儿1、3)采取重组人生长激素(rhHG)治疗后，身高增长速率与身高标准差(s)均较治疗前增加，IGF-1水平均较治疗前明显增高，甲状腺功能未见明显异常，未出现脊柱侧弯、头痛、关节疼痛等临床症状。患儿3出现暂时性空腹血糖受损。

NS可累及全身多个系统，主要临床表现为特殊面容、心脏缺陷、身材矮小，临床表现异质性大，易被临床误诊、漏诊。临床对合并特殊面容、身材矮小、心脏病变或其他脏器病变的患儿，应警惕NS可能。对合并身材矮小的NS患儿，采取rhHG治疗，可明显改善患儿身高。

To explore the clinical and genetic characteristics of Noonan syndrome (NS), and to evaluate the efficacy and safety of recombinant human growth hormone (rhGH) in treatment of children with NS.

Five patients with NS (patients 1-5) diagnosed at the First Affiliated Hospital of Bengbu Medical University from January 2021 to February 2023 were selected as research subjects. Among them, patients 1-4 were children with NS, and patients 3 and 4 were siblings. Patient 5 was the mother of patients 3 and 4. Due to slow growth of elder brother (patient 3), brothers (patients 3 and 4) and his mother (patient 5) underwent family genetic testing in the Department of Pediatric Endocrinology of our hospital, and no other relevant examinations were performed on patient 4 and 5. Patients 1-3 and patient 5 underwent high-throughput sequencing, and the results were verified by Sanger sequencing. Patient 4 only underwent Sanger sequencing. Clinical data of patients 1-5 were analyzed by retrospective research method, including clinical manifestations, examination results at admission, genetic test results, treatment and follow-up outcomes. The procedures followed in this study complied with the regulations of the Ethics Review Committee of the First Affiliated Hospital of Bengbu Medical University, and was approved by the committee (Approval No. 2023YJS141), and informed consent was obtained from all patients or their guardians.

The analysis results of patients 1-5 were as follows. ①History taking and physical examination results: 4 cases (patients 1-4) were male, and 1 case (patient 5) was female. Four cases (patients 1-4) had NS typical facial features, while 1 case (patient 5) had no obvious special facial features. Four cases (patients 1-3 and 5) were complicated with congenital heart disease (CHD), of which patient 1 was complicated with pulmonary artery stenosis, patient 2 was complicated with patent ductus arteriosus and ventricular septal defect, patient 3 was complicated with pulmonary artery stenosis and atrial septal defect, and patient 5 was complicated with atrial septal defect. Patients 1-3 had short stature. Patient 5 had didelphia and iron-deficiency anemia. ②Laboratory and imaging test results of patients 1-3: the levels of insulin and insulin-like growth factor (IGF)-1 of patient 3 were < 2 mIU/L and < 25 ng/mL, respectively, which both were lower than the normal values, while the other laboratory test results of patients 1-3 were all normal. MRI of the hypothalamus and pituitary gland for patient 3 suggested a left temporal arachnoid cyst, and patient 2 had mild scoliosis, while the other imaging test results of patients 1-3 were all normal. ③Genetic testing results: patient 1 had a likely pathogenic variant of the LZTR1 gene c. 851G>A(p.R284H) inherited from his father. Patient 2 had a pathogenic variant of the LZTR1 gene c. 1943-256C>T with both parents being wild-type. Patients 3-5 all had a pathogenic variant of the SOS1 gene c. 1654A>G(p.R552G). In patients 3 and 4, this variant was inherited from their mother (patient 5), while the origin of this variant in patient 5 was unknown. ④Treatment and follow-up results: two patients (patients 1 and 3) were treated with recombinant human growth hormone (rhGH), and showed an increased growth rate and height standard deviation (s) compared to pre-treatment, and with significantly elevated IGF-1 levels. No significant abnormalities in thyroid function were observed. No clinical symptoms such as scoliosis, headache, or joint pain appeared. Patient 3 experienced temporary impairment of fasting blood glucose.

NS can affect multiple systems throughout the body, with the main clinical manifestations being typical facial features, heart defects, and short stature. The heterogeneity of clinical manifestations is significant, making it prone to misdiagnosis and missed diagnosis in clinical settings. Clinicians should be vigilant to the possibility of NS for children with typical facial features, short stature, heart diseases, or other organ lesions. For NS children with short stature, treatment with rhGH can significantly improve their height.